No other single malignancy has been so consistently associated with osteolytic bone lesions and hypercalcemia as the HTLV associated adult T cell lymphoma (ATCL). The mechanism of the bone lesions and hypercalcemia may involve interactions between abnormal metabolism of vitamin D by HTLV infected cells in concert with the constitutive production of the lymphokine osteoclast activating factor. In this project, we plan to determine the mechanism of increased bone destruction and hypercalcemia associated with HTLV associated adult T cell lymphoma using bone resorption assays and studies of vitamin D metabolism in HTLV infected lymphoid cells. Our approach will be to identify the macromolecular bone resorbing factor using conventional protein purification techniques in association with identification of the factor using expression cloning of the mRNA species in a mammalian expression system. The studies on vitamin D metabolism will characterize the nature of the biologically active vitamin D metabolite which is produced by HTLV infected lymphoma cells and determine the relationship between production of this metabolite and the action of the macromolecular bone resorbing factor. Characterization of these factors produced by HTLV infected lymphoid cells which have powerful effects on bone cell metabolism should clarify the pathophysiology of this important clinical manifestation of this disease.